Achieving Long Timescale Sampling in Biomolecular Simulations

在生物分子模拟中实现长时间尺度采样

• 批准号: 0919983
• 负责人: Wei Yang
• 金额: $ 44.36万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0919983&HistoricalAwards=false
• 关键词: Achieving; Long; Timescale; Sampling; Biomolecular

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).The objective of this research is to develop and apply efficient simulation methods to quantitatively describe complex biomolecular phenomena that usually occur in longer timescale than what conventional methods can achieve. Molecular recognition such as protein-ligand recognition and large conformational transition are two key elements in biomolecular machines. Due to timescale limitation, quantitative understanding of these events via computer simulation has been very challenging. In this project, efficient generalized ensemble simulation methods will be developed and employed to enhance the sampling power of biomolecular simulations. The promise of this project is particularly ensured by a recent methodological development in the PI's lab: the orthogonal space random walk (OSRW) algorithm, which can uniquely realize collective environmental relaxation in a robust and efficient manner. Specifically, three aims will be targeted: (1) understanding protein-protein interactions and protein electrostatics via OSRW based free energy simulations; (2) developing a hybrid quantum mechanical/molecular mechanical (QM/MM) based OSRW sampling scheme to more accurately describe protein-ligand interactions; (3) developing OSRW based conformational sampling methods to predict protein functional dynamics. In recent years, the PI has made tremendous efforts in organizing workshops and meetings to connect computational biophysics and experimental biophysics and to bridge method developments and biological applications. Some of these workshops, for instance, Telluride workshop on sampling enhancement, have become standing ones. In particular, the PI has been putting enormous emphasis in building multi-layered environments for young scientists so that they can receive suitable education to carry out multi-disciplinary research. In order for the advanced methods that are recently developed in the groups of PI and others to be quickly absorbed by the scientific community, the PI edited a special issue on free energy simulation in Journal of Computational Chemistry in early 2009 and is co-writing a book that is focused on modern simulation methods and their hand-on application. In addition, the developed methods through this project will be released in the program CHARMM, which can be widely employed by general scientific community.

该奖项根据 2009 年美国复苏和再投资法案（公法 111-5）提供资金。这项研究的目的是开发和应用有效的模拟方法来定量描述通常在比传统方法更长的时间范围内发生的复杂生物分子现象。分子识别（例如蛋白质配体识别和大构象转变）是生物分子机器中的两个关键要素。由于时间尺度的限制，通过计算机模拟定量理解这些事件非常具有挑战性。在该项目中，将开发并采用高效的广义系综模拟方法来增强生物分子模拟的采样能力。 PI 实验室最近开发的方法特别确保了该项目的前景：正交空间随机游走（OSRW）算法，该算法可以以稳健且高效的方式独特地实现集体环境松弛。具体而言，将实现三个目标：（1）通过基于 OSRW 的自由能模拟了解蛋白质-蛋白质相互作用和蛋白质静电； （2）开发基于混合量子力学/分子力学（QM/MM）的OSRW采样方案，以更准确地描述蛋白质-配体相互作用； (3)开发基于OSRW的构象采样方法来预测蛋白质功能动态。近年来，PI 在组织研讨会和会议方面做出了巨大努力，以连接计算生物物理学和实验生物物理学，并在方法开发和生物应用之间架起桥梁。其中一些研讨会，例如关于采样增强的特柳赖德研讨会，已经成为常设研讨会。特别是，PI一直非常重视为年轻科学家建立多层次的环境，使他们能够接受适当的教育来开展多学科研究。为了使PI等团队最近开发的先进方法能够迅速被科学界吸收，PI于2009年初在Journal of Computational Chemistry上编辑了自由能模拟特刊，并正在与人合作撰写一本重点介绍现代模拟方法及其实际应用的书。此外，通过该项目开发的方法将在CHARMM程序中发布，可供广大科学界广泛采用。